ABSTRACT: Problem: The battle field against cancer is constantly in flux. Cancers metastasize and then require systemic therapy. They frequently become resistant to hormone therapies, biologicals, and small molecules - eventually depleting the arsenal of drugs that can be used against them. They are able to readily defeat therapeutics because initial treatments have side effects that limit dose and efficacy and also because they do not kill non-proliferating cells, such as cancer stem cells. This allows remaining tumor cells to ac- quire resistance and to regenerate tumors. Accordingly, there is an urgent need for treatments that can kill proliferating, non-proliferating, and drug resistant cancer cells, giving cancer patients a new paradigm to beat cancer. Solution: We have identified an agent with exactly these attributes: the clinical iron oxide nanoparti- cle Feraheme (FH). Many aggressive cancers have decreased levels of ferroportin, the sole known cellular exporter of iron, and subsequently higher intracellular iron. This cancer cell signature enables cell growth and proliferation. Yet, the increased redox-active iron in cells also generates deleterious hydroxyl radicals, making cancer cells susceptible to agents that further exhaust their antioxidant capacity. Feraheme is un- precedented in its ability to exploit this vulnerability. First, it increases redox-active intracellular iron and iron- catalyzed hydroxyl radicals in susceptible cancer cells with low ferroportin, leading to cell death. Second, it provides for an even higher tumor-specific effect, since normal cells are not only less susceptible in the first place, but also have the ability to detoxify introduced iron by using ferroportin to export it. Preliminary Data: This approach fulfills all the criteria for a pharmacologically highly promising target: We show that iron ho- meostasis is only perturbed in cancer to promote growth while normal cells have higher ferroportin and keep their iron homeostasis balanced. We demosntrate that Feraheme decompensates cancer cell?s antioxidant capacity, and we show we can use MRI to detect high iron levels, which could serving as a predictive bi- omarker of response. Lastly, we show that FH works synergistically with clinically used cancer drugs that increase oxidative stress, thereby significantly increasing tumor specificity while reducing side effects. Hy- pothesis: Given our preliminary data, we hypothesize that FH will kill even challenging cancers and that we will be able to predict efficacy with MRI based on the cancer cells? unique molecular signature of low ferroportin with high iron. By focusing initially on prostate cancer, our objective is to provide data for physi- cians how to best exploit Feraheme for hormone refractory prostate cancer, either off-label or through fo- cused clinical trials. Specific Aims:To test our hypotheses, we will (1) Explore the therapeutic index of Feraheme in vitro and in vivo, using xenografts and patient-derived prostate cancer organoids (2) evaluate sensitivity of noninvasive MR T2* imaging to predict the tumor response; and (3) evaluate use of Feraheme in combination with other anti-cancer agents.